Compositions comprising nitrofurantoin and uva ursi

ABSTRACT

Compositions and kits comprising nitrofurantoin and uva ursi are effective for treating infectious disorders, particularly urinary tract infections, cystitis, and pyelonephritis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.10/139,839 filed on May 7, 2002, now U.S. Pat. No. 6,521,270 allowed onOct. 22, 2002, which claims priority under Title 35, United States Code119(e) from Provisional application Ser. No. 60/297,274, filed Jun. 11,2001, now U.S. Pat. No. 6,521,270 issued Feb. 18, 2003.

TECHNICAL FIELD

The present invention relates to compositions and kits useful intreating infectious disorders.

BACKGROUND

Urinary tract infections (UTI) are a serious health problem affectingmillions of people each year. UTI infections account for about 10million doctor visits in the United States alone, with only respiratoryinfections occurring more often. Many remedies are taught for thetreatment of UTI.

In particular, nitrofurantoin is a well-known antibacterial compound andhas been used extensively as an active ingredient in antibacterialpharmaceutical compositions. Nitrofurantoin has been used successfullyfor many years for the treatment of UTI. Its presumed mode of action isbased upon its interference with several bacterial enzyme systems.However, the development of antibiotic resistant strains of microbescontinues to be problematic, thereby diminishing the effectiveness ofmany antibiotics.

Herbal remedies have also been used for the treatment of UTI. Inparticular, Arctostaphylos uva-ursi, also known as bearberry, has beenused as a urinary antiseptic. Indeed, teas and extracts of the leaveshave been used as urinary tract antiseptic for centuries. The leaves ofuva ursi contain hydroquinone derivates, mainly arbutin andmethyl-arbutin. Upon consumption, arbutin is hydrolyzed in gastric fluidto hydroquinone. In alkaline urine, hydroquinone is mildly astringentand is an effective antimicrobial agent. It has been suggested thatarbutin itself may contribute to the antiseptic activity of uva ursi.Despite this activity, in practice, large amounts of uva ursi must beconsumed for any significant effect to occur and the urine must bealkalinized.

For the foregoing reasons, there is a continuing need to find moreeffective ways to treat UTI. Furthermore, there is a continuing need tofind more effective ways to enhance the efficacy of existingantimicrobial compounds such as nitrofurantoin against UTI-causingmicrobes, particularly those resistant strains.

SUMMARY OF THE INVENTION

The present invention provides a composition comprising a safe andeffective amount of nitrofurantoin and uva ursi. The invention furtherprovides for a kit comprising (a) nitrofurantoin in a unit dose form;(b) uva ursi in a unit dose form; and (c) a package containingcomponents (a) and (b). The administration of a composition or a unitdose form of a kit of the present invention to a subject in needthereof, is effective for the prevention and treatment of infectiousdisorders such as UTI, acute cystitis, and pyelonephritis. The inventionis also effective for treating upper-gastrointestinal disorders.

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION I. Compositions and Kits

In accordance with the present invention, an antimicrobial compositionand kit containing nitrofurantoin can achieve a higher efficacy ofantimicrobial activity if complemented by uva ursi.

Furthermore, the composition and kit comprising nitrofurantoin and uvaursi according to the present invention may exhibit synergism bylowering the MIC (minimum inhibitory concentration) and even FIC(fractional inhibitory concentration) of nitrofurantoin.

The compositions of the present invention comprise: (a) a safe andeffective amount of nitrofurantoin; (b) a safe and effective amount ofuva ursi; and (c) optionally, a pharmaceutically-acceptable carrier.

The kits of the present invention comprise: (a) nitrofurantoin in a unitdose form; (b) uva ursi in a unit dose form; and (c) a packagecontaining components (a) and (b). In one mode, the kit of the presentinvention contains nitrofurantoin and uva ursi in a single unit doseform. In another mode, nitrofurantoin and uva ursi are in separate unitdose forms. In either instance, a plurality of doses can be present toprovide prevention or treatment over a period of several days, or weeks.Still another mode, instructions to the kit are included.

As used herein, “nitrofurantoin” includes the compoundN-(5-nitro-2-furfurylidene)-1-aminohydantoin, as well as itspharmaceutically acceptable salts, hydrates, and complexes. (See “6696.Nitrofurantoin”, The Merck Index, 12th ed. (1996, pp. 1134).Nitrofurantoin “complexes” refer to chemical complexes of nitrofurantoinwith other chemical constituents that result in entities that retain atleast a substantial portion of the antimicrobial activity ofnitrofurantoin. Examples of such complexes includenitrofurantoin-phthaloyl glycine and nitrofurantoin-phthaloylaminocaproic acid. A method for preparing nitrofurantoin is disclosed inU.S. Pat. No. 2,610181, to Hayes, issued Sep. 9, 1952. A method forpreparing macrocrystalline nitrofurantoin is disclosed in U.S. Pat. No.3,401,221, to Brogmann et al., issued Sep. 10, 1968. See also, U.S. Pat.Nos. 2,898,335; 2,927,110; 3,007,846; and 3,446,802 to Michels; Gever &O'Keefe; Gever & Vincent; and Michels issued Aug. 4, 1959; Mar. 1, 1960;Nov. 7, 1961; and May 27, 1969 respectively.

“Uva ursi” is a plant, including plant parts such as leaves, stems,berries roots, flowers and the like, or an extract thereof ofArctostaphylos uva-ursi, and related members of its family Ericaceaeincluding, but not limited to, Vaccinium, Arctostaphylos, Gaultheria,and Gaylussacia. Preferred species include, Arctostaphylos adenotricha,and Arciostaphylos coacrylis, and Arctostaphylos uva-ursi mostpreferably Arctostaphylos uva-ursi. Mixtures of Ericaceae plants and /orextracts may also be used. Other names of A. uva-ursi include:beargrape, kinnikinnick, mealberry, mountain box, mountain cranberry,redberry leaves, sagackhomi, sandberry, hogberry, manzanita andbearberry.

A well-known homeopathic treatment for acute cystitis has been the useof uva ursi. It has now been found through in vitro microbiologicaltesting that a combination of nitrofurantoin and uva ursi (hereinafterreferred to as “the combination”) results in a significant reduction inthe minimal inhibitory concentration (MIC) required to inhibit thegrowth of certain urinary tract pathogens (see “IV. Data”).Specifically, when the combination is tested against Pseudomonas,Porteus, Serratia, and Klebsiella there was a significant decrease inthe MIC values for nitrofurantoin. Historically, all of these pathogensare known to be moderately or highly resistant to nitrofurantoin.Additionally, there is synergistic activity seen against Serratia asevidenced by the concurrent lowering of MIC for uva ursi. Together theseresults suggest that the combination may beneficial in the treatment ofinfectious disorders such as acute cystitis caused by pathogens notadequately eradicated by either nitrofurantoin or uva ursi alone.

As discussed above, the combination is effective for treating andpreventing infectious disorders. Thus, the combination can be formulatedinto pharmaceutical compositions or packaged as a kit. Standardpharmaceutical formulation techniques are used, such as those disclosedin Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., latest edition.

A “safe and effective amount” of nitrofurantoin and uva ursi is anamount, taken concurrently, that is effective to treat an infectiousdisorder in an animal, preferably a mammal, more preferably a canine,feline, or human, still more preferably a human subject, without undueadverse effects (such as toxicity, irritation, or allergic response),commensurate with a reasonable benefit/risk ratio when used in themanner of the present invention. The term “concurrently,” as usedherein, means that uva ursi and nitrofurantoin are administered within24 hours of each other, preferably conjointly. The specific “safe andeffective amount” will, obviously, vary with such factors as theparticular infectious disorder being treated, the physical condition ofthe patient, the duration of treatment, the nature of concurrent therapy(if any), the specific dosage form to be used, the carrier employed, thesolubility of dose form, and the particular dosage regimen.

In addition to the safe and effective amounts of the combination, thecompositions of the present invention optionally contain apharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier,” as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable or administration to an animal, preferably a mammal,more preferably a canine, feline, or human, still more preferably ahuman. The term “compatible,” as used herein, means that the componentsof the composition are capable of being commingled with nitrofurantoinand uva ursi, and with each other, in a manner such that there is nointeraction that would substantially reduce the pharmaceutical efficacyof the composition under ordinary use situations.Pharmaceutically-acceptable carriers must, of course, be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the animal, preferably a mammal, more preferably afeline, canine, and human, even more preferably a human being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are: sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the combination is basically determined by the way thecomposition is to be administered.

If the subject composition is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with a blood-compatible colloidal suspending agent, the pH of which hasbeen adjusted to about 7.4.

In particular, pharmaceutically-acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers. isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

The compositions and kits of the present invention are preferablyprovided in unit dosage form. As used herein, a “unit dosage form” is anamount of the combination that is suitable for administrationconcurrently to an animal, preferably a mammal, more preferably acanine, feline, or human, still more preferably a human subject, in asingle dose, according to good medical practice. These unit dosage formspreferably contain from about 1 mg (milligram) to about 10,0000 mg, morepreferably from about 10 mg to about 3,000 mg, more preferably fromabout 20 mg to about 2,000 mg of the combination. In an embodiment of akit of the present invention where nitrofurantoin and uva ursi are inseparate unit dose forms, the two separate unit dose forms cumulativelycontain the combination in the above-identified ranges.

The compositions of the present invention may be in any of a variety offorms, suitable, for example, for oral, rectal, topical, nasal, ocularor parenteral administration. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the antimicrobialactivity of the combination. The amount of carrier employed inconjunction with the combination is sufficient to provide a practicalquantity of material for administration per unit dose of thecombination. Techniques and compositions for making dosage forms usefulin the methods of the present invention are described in the followingreferences: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,editors, 1979); Lieberman et al., Phannaceutical Dosage Forms: Tablets(1981); and Ansel, Introduction to Pharnaceutical Dosage Forms 2^(nd)Edition (1976).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, preferably fromabout 10% to about 95%, and more preferably from about 25% to about 50%by weight, of the combination. Typical ratios ranges of uva ursi tonitrofurantoin are about 1:2 to about 1:100, preferably about 1:5 toabout 1:40. Tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, or multiple-compressed.containing suitable binders, lubricants, diluents, disintegratingagents, coloring agents, flavoring agents, flow-inducing agents, andmelting agents. One form of tableting technology that may be applicableto the present invention, particularly a unit form of uva ursi, is aliquid/liquid extract developed by Janssen Pharmaceutica Inc. and isidentified by the trade name Quicksolv®. This technology is fullydescribed in U.S. Pat. No. 5,215,756, to Gole et al., issued Jun. 1,1993. Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules, and effervescent preparations reconstitutedfrom effervescent granules, and containing suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability which are not critical for the purposes of the presentinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, Avicel® RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-pendent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit®coatings, waxes and shellac.

Alternatively, the compositions of the present invention may be achievedby incorporating unit dose forms of the combination into freeze-dried orlyophilized tablets. Freeze-drying or lyophilization facilitatesdisintegration of the composition by rapid permeation by the aqueousmedia, promoting timely delivery of the produce. Suitable methods offreeze-drying are well known in the art and commonly employed. Anysuitable conventional method of freeze-drying may be utilized. Apreferable method of freezing and drying is to fast freeze thecomposition and then dry the composition to a final moisture content ofabout 2% to about 5%. Suitable methods of freeze-drying and productionare taught by U.S. Pat. No. 4,642,903, Feb. 17, 1987, to Davies, U.S.Pat. No. 4,946,684, Aug. 7, 1990, to Blank et al., U.S. Pat. Nos.4,305,502 and 4,371,516, issued Dec. 15, 1981 and Feb. 1, 1983respectively, to Gregory et al., and U.S. Pat. No. 5,188,825, Feb. 23,1993, to Iles et al.

Similarly, unit dose forms of the combination may be vacuum dried.Vacuum drying involves at least the partial drying of compositions attemperatures above compositions' collapse temperature. Freeze drying, onthe other hand, involves the drying of composition at temperatures belowthe composition's collapse temperature. Any suitable method of vacuumdrying may be used. Suitable vacuum drying processes are described inU.S. Pat. No. 5,298,261, to Pebley et al., issued Mar. 29, 1994.

Other compositions useful for attaining systemic delivery of thecombination include topical (e.g., transdermal “patch”), sublingual,buccal, suppository, and nasal dosage forms. Such compositions typicallycomprise one or more of soluble filler substances such as sucrose,sorbitol and mannitol; and binders such as acacia, microcrystallinecellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.Glidants, lubricants, sweeteners, colorants, antioxidants and flavoringagents disclosed above may also be included.

The pH of the compositions of the present invention may be adjusted byaddition of a pharmaceutically-acceptable acid or base. Suitable acidsinclude, for example, hydrochloric acid and carboxylic acids such ascitric acid, tartaric acid and succinic acid. Suitable bases include,for example, the oxides and hydroxides of calcium, potassium, sodium andmagnesium, alkaline quanternary compounds, alkaline amino acids, andmixtures thereof. The compositions of the present invention arepreferably pH balanced and/or buffered between about 5 to about 8.

The compositions of the present invention may optionally includeadditional antimicrobrial agents. Non-limiting examples include: sulfadrugs (sulfonamides), amoxicillin, cephalosporins,trimethoprim-sulfamethoxazole, and doxycycline.

The compositions of the present invention may optionally include otherdrug actives. For example, analgesics may also be included such asacetaminophen, acetyl salicylic acid, indomethacin and optically activeisomers or racemates of ibuprofen, naproxen, flurbiprofen, carpofen,tiprofenic acid, cicloprofen, ketoprofen, ketorolac, etodolac,indomethacin, sulindac, fenoprofen, diclofenac, piroxicam, benzydomine,nabumetone, their pharmaceutically acceptable salts and mixturesthereof. Another example, gastrointestinal agents may also be includedsuch as anticholinergics including atropine, clidinium and dicyclomine;antacids including aluminum hydroxide, bismuth subsalicylate, bismuthsubcitrate, simethicone, calcium carbonate and magaldrate; H₂-receptorantagonists including cimetidine, famotidine, nizatidine and ranitidine;laxatives including: docusate. phenolphthalein and casanthrol;gastroprotectants including sucralfate and sucralate humidgel;gastrokinetic agents including metoclopramide and cisapride; proton pumpinhibitors including omeprazole and antidiarrheals including:diphenoxylate, kaolin pectin, attapulgite and loperamide.

The compositions the present invention may optionally include additionalplant extracts. Such plants or extracts include Echinacea, allium,bucha, juniper, ginseng, allicin, chlorella, algin, plants under theEricaceae family, asparagus, birch, couch grass, goldenrod, horsetail,java tea, lovage, parsley, spiny restharrow, and the like.

The compositions of the present invention may optionally includenutritional supplements such as bromelain, vitamin A, and vitamin C.

As previously stated, in one mode, the unit dose forms of nitrofurantoinand uva ursi of the kits of the present invention are in separate unitdose forms. Non-limiting examples of nitrofurantoin in a separate unitdose form include: nitrofurantoin crystals per U.S. Pat. No. 5,332,832,to Cazer et al., issued Jul. 26, 1994; liquid suspensions ofnitrofurantoin per U.S. Pat. No. 5,178,880, to Shahi et al., issued Jan.12, 1993; dual-action tablet as illustrated in U.S. Pat. No. 5,032,406,to Dansereau & Kane, issued Jul. 16, 1991; nitrofurantoin dosage formper U.S. Pat. No. 4,772,473, to Patel et al., issued Sep. 20, 1988; andnitrofurantoin sustained release tablet per U.S. Pat. No. 4,122,157, toHuber, issued Oct. 24, 1978. A preferred unit dose form ofnitrofurantoin is Macrobid® as exemplified in U.S. Pat. No. 4,772,473.

Non-limiting examples of uva ursi in a separate unit dose form includewhole plant, including leaves (preferably), stems, shoots, berries,roots, and flowering parts, these can be ground, shredded or otherwisemacerated and reduced in size for convenient use, and extracts thereof,as well as those unit dose forms commercially available includingextracts, powders, capsules, gel caps, tablets, liquid, suspension, andtincture forms. Extracts can include both aqueous and organic solventextract, e.g. ethanol, if desired, the extract can be dried and theresulting dried extract employed herein. For example, uva ursi leaf anduva ursi extract are available from Gaia Herbs, Inc. in Brevard, N.C.and Nature's Answer®, Springville, Utah; Green Kingdon Herbs. Bay City,Mich. Also encompassed are those commercially available products thatcontain at least some uva ursi in part. For example, many teas containuva ursi such as Gerard House Herbal powder No. 8®, Potter's Kas-bahHerb®; Potter's Sciargo Herb®, and Wellwoman Herbs®. Also furtherencompassed are capsules and tablets containing uva ursi marketed forremedies such as for backaches and rheumatic pain. An example isMelfade®, by Pentapharm Ltd, Basel Switzerland.

II. Methods of Administration.

The compositions and unit dose form of kits of the present invention canbe administered to treat infectious disorders in a subject in needthereof. As used herein, an “infectious disorder” is any disordercharacterized by the presence of a microbial infection. Preferredmethods of the present invention are the treatment of bacterialinfections, particularly genitourinary infections, and gastrointestinalinfections. Included within infectious disorders are generalized UTI,acute cystitis, and pyelonephritis. Included within bacterial infectionsare those infections caused by Pseudomonas aeruginosa, Serratiamarcescens, Enterococcus Faecalis, Klebsiella pneumoniae, Porieusmirabilis, Escherichia coli, and/or Staphylococcus saprophyticus.

One skilled in the art would readily identify an infectious disorder.For example, the diagnostic techniques for a ULI include, but are notlimited to, palpation over the kidney urinalysis, urine culture (cleancatch), urine culture (catheterized specimen), blood culture,intravenous pyelogram scan, computed tomography scan, voidingcystourethrogram, renal ultrasound, renal scan, and renal biopsy.

Symptoms of infectious disorder are readily identifiable by thoseskilled in the art. For example, the symptoms of UTI include, but arenot limited to, pressure in the lower pelvis, painful urination(dysuria), frequent need to urinate, urgent need to urinate, need tourinate at night, cloudy urine, blood in the urine (hematuria), and foulor strong urine odor.

The term “treatment” is used herein to mean that, at a minimum,administration of a compound or kit of the present invention mitigatesan infectious disorder in a mammalian subject, preferably in humans.Thus, the term “treatment” includes: preventing an infectious disorderfrom occurring in a mammal, particularly when the mammal is predisposedto acquiring the infectious disorder, but has not yet been diagnosedwith the disease, inhibiting the infectious disorder; and/or alleviatingor reversing the infectious disorder. Insofar as the methods of thepresent invention are directed to preventing an infectious disorder, itis understood that the term “prevent” does not require that theinfectious disorder be completely thwarted. (See Webster's NinthCollegiate Dictionary.) Rather, as used herein, the term “preventing”refers to the ability of the skilled artisan to identify a populationthat is susceptible to infectious disorders, such that administration ofthe compounds and kits of the present invention may occur prior to theonset of the symptoms of the infectious disorder. The population that isat risk for an infectious disorder, particularly an UTI, include thosewho are subjected to: an obstruction of the bladder or urethra withresultant stasis of urine, insertion of instruments into the urinarytract (such as cateterization or cystoscopy), pregnancy, diabetes, and ahistory of analgesic nephropathy or reflux nephropathy. The elderlypopulation is at increased risk for developing an UTI due to lack ofmobility and/or incomplete emptying of the bladder associated with suchconditions are benign prostatic hyperplasia, prostatitis, and urethralstrictures.

Thus, the patient population is identifiable and could receive theadministration of a composition or unit dose form of a kit of thepresent invention before progression of the disease. Thus, progressionof the infectious disorder in such individuals would be “prevented.”

The compositions and kits of the present invention are also useful forprophylactic or acute treatment. The compositions and dose form of kitsof the present invention are administered in any way the skilled artisanin the field of medicine or pharmacology would desire. It is immediatelyapparent to the skilled artisan that preferred routes of administrationdepend on the infectious disorder being treated and the dosage formchosen. A preferred route for systemic administration includesperorally.

The preferred methods of the present invention also include methods forthe treatment and prophylaxis of upper-gastrointestinal disordersmediated by Campylobacter pylori. For example, the compositions and unitdose form of kits of the present invention can be used for theprevention and treatment of C. pylori mediated ulcers. Such methods andothers are generally described in European Patent Publication 219,912,Kraft et al. published Apr. 29, 1987.

The compositions and unit dose form of kits of the present invention canbe administered systemically. Systemic application includes any methodof introducing a composition or unit dose form of a kit of the presentinvention into the tissues of the body, for example, epidural,intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous,sublingual, rectal, and oral administration. The compositions and unitdose form of kits of the present invention are preferably administeredorally.

The specific dose of a composition or unit dose form of a kit of thepresent invention to be administered, as well as the duration oftreatment, are mutually dependent. The dosage and treatment regimen willalso depend upon such factors as the route of administration, the typeof dosage form used, the infectious agent present, the ability of thecombination to reach and sustain effective levels at the site ofinfection, the nature and extent of other infections (if any), thepersonal attributes of the subject (such as weight), compliance with thetreatment regimen, and the presence and severity of any side effects ofthe treatment.

For systemic administration of the compositions or unit dose form ofkits, typically for a human adult (weighing approximately 70 kilograms),from about 1 mg to about 10,000 mg, preferably from about 10 mg to about5000 mg of the compositions or unit dose form of kits are administeredper day.

Treatment regimens preferably extend from about once to about five timesdaily, for about 1 to about 56 days, preferably for about 3 to about 10days,

It is understood that these dosage ranges are by way of example only,and that daily administration can be adjusted depending on the factorslisted above.

III. Data

A. Introduction

Antimicrobial combinations are sometimes used to provide broad-spectrumtreatment. Combinations of antimicrobial agents may be chosen because apathogen is resistant to inhibition and/or killing by conventional dosesof a siraje agent but susceptible to the same agent in combination withanother agent. Nitrofurantoin has broad-spectrum activity againstGram-positive and Gram-negative bacteria. Particularly the common UTIpathogens. In particular, nitrofurantoin is active against Gram-positivecocci such as Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus and Enterococcus faecalis. Over 90% ofEscherichia coli and many coliform bacteria are susceptible. However,only ⅓ of Enterobacter and Klebsiella isolates are susceptible.Pseudomonas and most Proteus species are resistant.

The present study evaluated combination therapy with nitrofurantoin anduva ursi (specifically, Arctostaphylos uva-ursi) extract and determinedthe effectiveness of such a combination approach. The study alsoevaluated if there was synergism between nitrofurantoin and uva ursi.“Synergism” is a positive interaction between two drugs; the combinedeffect of the drugs being examined is greater than the expected resultsbased on their independent effects when the drugs are used separately.Synergism should be distinguished from “additivity,” which is defined,as the effect of two drugs used together is equal to the sum of theeffects of each drug used separately. “Antagonism” is the effect of twodrugs used together is less than the sum of the effects of each drugused separately.

The checkerboard (or chessboard) method is used to assess theantimicrobial combination in vitro against the following selection ofGram-positive and Gram-negative pathogens including: Escherichia coli,Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens,Staphylococcus saprophyticus, Pseudomonas aeruginosa, and Enterococcusfaecalis. It was found that the combination of nitrofurantoin with uvaursi is capable of reducing the MIC of nitrofurantoin again nearly allisolates tested. Furthermore, the combination of nitrofurantoin and uvaursi is synergistic against four of the seven species tested, inparticular E. coli, S. marcescens, P. mirabilis, and P. aeruginosa.

Without being limited by theory, it is believed that, the synergybetween nitrofurantoin and uva ursi is actually between nitrofurantoinand either arbutin, methyl-arbutin and/or hydroquinone. This issurprising in light of the antagonism that has been reported betweennitrofurantoin and other antibiotics such as reported in Shah, S. & D.Greenwood, “Interactions between antibacterial agents of the quinolonegroup and nitrofurantoin,” Journal of Antimicrobial Chemotherapy, Vol.21, pp. 41-48 (1998).

B. Materials and Methods

Utilizing the checkerboard (or chessboard) method, concentrations ofnitrofurantoin monohydrate (0.5-256 μg/mL) and uva ursi (specifically,Arctostaphylos uva-ursi) extract (0.125-8 μg/mL in 40% (v/v) ethanol)used ranged from four to five dilutions below the pre-test MIC for eachdrug to two dilutions above the pre-test MIC for each drug.

The MIC was determined for each isolate for both nitrofurantoin and theuva ursi prior to the checkerboard testing; using approved standardNational Committee for Clinical Laboratory Standards (hereinafter“NCCLS”) methods for microbroth dilution. Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;Approved Standard (Fifth Edition) (2000). These standards are asfollows:

Organism Final (10 isolates each Inoculum Inoculum Test Incubationthereof) Preparation Size Medium Conditions P aeruginosa Colonies taken1 × 10⁶ Cation- 35° C., S. marcescens from overnight CFU/ml adjusted18-24 E. faecalis growth on 5% Mueller- hours K. pneumoniae sheep bloodHinton P. mirabilis agar and Broth E. coli suspended to a S.saprophyticus 0.5 McFarland Standard

Nitrofurantoin was added to cation-adjusted Mueller-Hinton Broth(hereinafter “CAMHB”) and dissolved. Serial doubling dilutions wereperformed in CAMHB providing concentrations ranging from 0.5 μg/ml to256 μg/ml.

The uva ursi extract was serially diluted in water. For each testconcentration, the final dilution was performed in CAMHB providingdilutions of 1:20 to 1:2048.

Synergy panels were designed for each isolate based on pre-test MICs forboth nitrofurantoin and uva ursi extract. Following testing, the FICindex was calculated for each isolate panel to determine whethersynergy, additivity, or antagonism occurred.${\frac{(A)}{( {MIC}_{A} )} + \frac{(B)}{( {MIC}_{B} )}} = {{{FIC}_{A} + {FIC}_{B}} = {{FIC}\quad {Index}}}$

wherein: (A) is the concentration of drug A in a well that is the lowestinhibitory concentration in its row; (MIC_(A)) is the MIC of theorganism to drug A alone; and B) and (MIC_(B)) are defined in the sameway for drug B.

For synergy, the FIC index is 0.5. For additivity, the FIC index is 1.For antagonism, the FIC index is 2.

The NCCLS reference strain for E. coli, ATCC 25922, was used for qualitycontrol with a MIC range of 4-16 μg/ml. There are no NCCLS referencestrains for nitrofurantoin for the remaining test organisms.

C. Results

a. Pseudomonas aeruginosa.

Pre-test MIC were all >512 μg/ml for nitrofurantoin and ranged fromdilutions of 1:80 to 1:160 for uva ursi. In the presence of uva ursi,nitrofurantoin MIC ranged from 0.25→512 μg/ml. One out of ten isolatesdemonstrated synergy, four demonstrated additivity, and five showed noeffect with the uva ursi and nitrofurantoin combinations.

TABLE 1-1 Pre test MIC of nitrofurantoin and uva ursi among P.aeruginosa. Isolate ID Nitrofurantoin MIC (μg/ml) Dilution ratio uvaursi 1 >512 1:80 2 >512 1:80 3 >512 1:80 4 >512 1:80 5 >512 1:80 6 >5121:80 7 >512 1:80 8 >512 1:80 9 >512 1:80 10  >512  1:160

TABLE 1-2 Test results for P. aeruginosa showing lowest fractionalinhibitory concentration MIC (μg/ml) Dilution MIC for Uva ursi IsolateNitrofuran- ratio combina- Dilution ratio ID toin uva ursi tion* at MICResult 1 >512 1:80 256  1:160 Additivity 2 >512  1:160 >512 1:80 NE^(‡)3 >512 1:80 >512 1:80 NE 4 >512 1:80 >512 1:80 NE 5 >512 1:40 0.25 1:80Synergy 6 >512 1:80 >512 1:80 NE 7 >512 1:80 256  1:160 Additivity8 >512 1:80 256  1:160 Additivity 9 >512  1:160 >512  1:160 NE 10    512 1:160 256  1:320 Additivity *When synergy was not observed, the MIC forthe combination was selected based on the nitrofurantoin MIC thatprovided the FIC value closest to 0.5. In the case where FIC values werethe same, the MIC for the combination was based on the lowestnitrofurantoin MIC. ‡“NE” = No effect

b. Serratia marcescens

Pre-test MIC ranged from 64-512 μg/ml for nitrofurantoin and dilution of1:40 to 1:80 for uva ursi extract. In the presence of uva ursi,nitrofurantoin MIC ranged from 4-64 μg/ml. With uva ursi andnitrofurantoin combinations, four out of ten isolates demonstratedsynergy, one additivity, and five had FIC values between synergy andadditivity. Regardless of FIC calculations for synergy, the uva ursi andnitrofurantoin combination was at least 8-fold more active thannitrofurantoin by itself. Only one isolate demonstrated less than 4-foldincreased activity in the presence of the uva ursi.

TABLE 1-3 Pre-test MIC of nitrofurantoin and uva ursi among S.marcescens Isolate ID MIC (μg/ml) Nitrofurantoin Dilution ratio uva ursi11 256 1:80 12 256 1:40 13 512 1:80 14 256 1:40 15 256 1:40 16  64 1:8017 256 1:40 18 256 1:40 19 256 1:80 20 256 1:80

TABLE 1-4 Test results for S. marcescens showing lowest fractionalinhibitory concentration MIC (μg/ml) Dilution MIC for Uva ursi IsolateNitrofuran- ratio combina- Dilution ratio ID toin uva ursi tion* at MICResult 11 256 1:80 32  1:160 0.63 12 128 1:40 16 1:80 0.63 13 256 1:8064  1:160 0.75 14 256 1:40 8 1:80 Synergy 15 256 1:40 4 1:80 Synergy 16 64  1:320 32  1:640 Additivity 17 256 1:40 64  1:160 Synergy 18 2561:80 64  1:160 0.75 19 256 1:80 32  1:160 0.63 20 256 1:80 64  1:320Synergy *When synergy was not observed, the MIC for the combination wasselected based on the nitrofurantoin MIC that provided the FIC valueclosest to 0.5. In the case where FIC values were the same, the MIC forthe combination was based on the lowest nitrofurantoin MIC.

c. Enterococcus faecalis

Pre-test MIC ranged from 8-64 μg/ml for nitrofurantoin and dilutions of1:160 to 1:5120 for uva ursi. In the presence of uva ursi.nitrofurantoin MIC ranged from 4-16 μg/ml. With the uva ursi andnitrofurantoin combinations, one out of ten isolates showed additivity,and nine demonstrated no change.

TABLE 1-5 Pre-test MIC of nitrofurantoin and uva ursi among E. faecalisIsolate ID MIC (μg/ml) Nitrofurantoin Dilution ratio uva ursi 21 641:280 22 16 1:640 23 16 1:160 24 8  1:1280 25 16 1:320 26 32  1:1280 278 1:320 28 32  1:1280 29 16  1:2560 30 8  1:5120

TABLE 1-6 Test results for E. faecalis showing lowest fractionalinhibitory concentration MIC (μg/ml) Dilution MIC for Uva ursi IsolateNitrofuran- ratio combina- Dilution ratio ID toin uva ursi tion at MICResult 21 16 1:640 8 1:1280 Additivity 22 16 1:320 16 1:320  NE^(‡) 2316 1:80  4 1:160  0.75 24 16 >1:320   16 >1:320  NE 25 16 1:160 161:160  NE 26 16 1:320 8 1:1280 0.75 27 16 1:160 16 1:160  NE 28 16 1:1280 16 1:1280 NE 29 16  1:1280 16 1:1280 NE 30  8  1:2560 8 1:2560NE *When synergy was not observed the MIC for the combination wasselected based on the nitrofurantoin MIC that provided the FIC valueclosest to 0.5. In the case where FIC values were the same, the MIC forthe combination was based on the lowest nitrofurantoin MIC. ‡“NE” = Noeffect

d. Klebsiella pneumoniae

Pre-test MICs ranged form 4 to >512 μg/ml for nitrofurantoin anddilutions of 1:40 to 1:80 for the uva ursi. In the presence of uva ursi,nitrofurantoin MICs ranged from 2-256 μg/ml. With the uva ursi andnitrofurantoin combinations, five out of ten isolates demonstratedadditivity, one showed no effect and four had FIC values between synergyand additivity. Regardless of FIC calculation for synergy, the uva ursiand nitrofurantoin combination was at least 2-fold more active thannitrofurantoin by itself, in nine out of ten isolates tested.

TABLE 1-7 Pre test MIC of nitrofurantoin and uva ursi among K.pneumoniae Isolate ID MIC (μg/ml) Nitrofurantoin Dilution ratio uva ursi31 128 1:40 32 4 1:40 33 32 1:40 34 32 1:40 35 32 1:40 36 64 1:40 37 641:40 38 32 1:80 39 >512 1:40 40 128 1:40

TABLE 1-8 Test results for K. pneumoniae showing lowest fractionalinhibitory concentration MIC (μg/ml) Dilution MIC for Uva ursi IsolateNitrofuran- ratio combina- Dilution ratio ID toin uva ursi tion* at MICResult 31 256 1:40 256 1:40 NE‡ 32 4 1:40 2 1:80 Additivity 33 64 1:4016 1:80 0.75 34 32 1:40 16 1:80 Additivity 35 32 1:40 16 1:80 Additivity36 64 1:40 16 1:80 0.75 37 64 1:40 16 1:80 0.75 38 32  1:160 16  1:320Additivity 39 >512 1:40 128 1:80 0.75 40 128 1:40 64 1:80 Additivity*When synergy was not observed, the MIC for the combination was selectedbased on the nitrofurantoin MIC that provided the FIC value closest to0.5. In the case where FIC values were the same, the MIC for thecombination was based on the lowest nitrofurantoin MIC. ‡“NE” = Noeffect

e. Proteus mirabilis.

Pre-test MIC ranged from 16 to >512 μg/ml for nitrofurantoin anddilutions of 1:40 to 1:320 for the uva ursi. In the presence of uvaursi, nitrofurantoin MIC ranged from 2-128 μg/ml. With the uva ursi andnitrofurantoin combinations, four out of ten isolates demonstratedsynergy. The remaining six isolates had FIC values between synergy andadditivity. Regardless of FIC calculations for synergy, the uva ursi andnitrofurantoin combination was two to seven dilutions more active thannitrofurantoin by itself.

TABLE 1-9 Pre test MIC of nitrofurantoin and uva ursi among P. mirabilisIsolate ID MIC (μg/ml) Nitrofurantoin Dilution ratio uva ursi 41 1281:160 42 16 1:160 43 256 1:160 44 >512 1:160 45 32 1:320 46 256 1:320 47256 1:160 48 128 1:320 49 256 1:40  50 128 1:160

TABLE 1-10 Test results for P. mirabilis showing lowest fractionalinhibitory concentration Dilution MIC (μg/ml) ratio MIC for Uva ursiIsolate Nitrofuran- uva ursi combina- Dilution ratio ID toin extracttion* at MIC Result 41 128 1:160 32 1:640 Synergy 42 26 1:320 4 1:6400.75 43 256 1:160 32 1:640 Synergy 44 >512 1:160 64 1:320 0.63 45 321:160 8 1:640 Synergy 46 256 1:320 128  1:2560 0.63 47 256 1:160 641:640 Synergy 48 128 1:320 32 1:640 0.75 49 128 1:160 8 1:320 0.56 50128 1:160 2 1:320 0.52 *When synergy was not observed, the MIC for thecombination was selected based on the nitrofurantoin MIC that providedthe FIC value closest to 0.5. In the case where FIC values were thesame, the MIC for the combination was based on the lowest nitrofurantoinMIC.

f. Escherichia coli

Pre-test MIC ranged from 32 to >512 μg/ml for nitrofurantoin anddilutions of 1:40 to 1:80 for the uva ursi. In the presence of uva ursi,nitrofurantoin MIC ranged from 4-128 μg/ml. With the uva ursi andnitrofurantoin combinations, six out of ten isolates demonstratedsynergy. The remaining four isolates had FIC values between synergy andadditivity. Regardless of FIC calculations for synergy, the uva ursi andnitrofurantoin combination was one to six dilutions more thannitrofurantoin by itself, with six isolates at least 4 dilutions moreactive than nitrofurantoin by itself.

TABLE 1-11 Pre-test MICs of nitrofurantoin and uva ursi among E. coliIsolate ID MIC (μg/ml) Nitrofurantoin Dilution ratio uva ursi 51 >5121:80 52 >512 1:80 53 >512 1:40 54 32 1:40 55 256 1:80 56 128 1:80 57 641:40 58 128 1:40 59 >512 1:80 60 64 1:40

TABLE 1-12 Test results for E. coli showing lowest fractional inhibitoryconcentration MIC (μg/ml) Dilution MIC for Uva ursi Isolate Nitrofuranratio combina- Dilution ratio ID toin uva ursi tion* at MIC Result51 >512 1:80 128 1:320 Synergy 52 >512 1:80 32 1:160 0.56 53 32 1:40 41:80  0.63 54 32 1:40 8 1:160 Synergy 55 128  1:160 64 1:640 0.75 56 641:40 16 1:160 Synergy 57 64 1:40 16 1:160 Synergy 58 128 1:80 64 1:6400.63 59 >5122 1:80 128 1:320 Synergy 60 64 1:40 16 1:320 Synergy *Whensynergy was not observed, the MIC for the combination was selected basedon the nitrofurantoin MIC that provided the FIC value closest to 0.5. Inthe case where FIC values were the same the MIC for the combination wasbased on the lowest nitrofurantoin MIC.

g. Staphylococcus saprophyticus

Pre-test MIC ranged from 8 to 32 μg/ml for nitrofurantoin and dilutionsof 1:160 to 1:1280 for the uva ursi. In the presence of uva ursi,nitrofurantoin MIC ranged from 5-8 μg/ml. With the uva ursi andnitrofurantoin combinations, three out of ten isolates demonstratedsynergy. The remaining seven isolates had MIC values between synergy andadditivity. Regardless of FIC calculations for synergy, the uva ursi andnitrofurantoin combination was one to four dilutions more thannitrofurantoin by itself.

TABLE 1-13 Pre-test MIC of nitrofurantoin and uva ursi among S.saprophyticus Isolate ID MIC (μg/ml) Nitrofurantoin Dilution ratio uvaursi 61 16 1:320 62 16 1:320 63 16 1:320 64 32 1:320 65 16 1:160 66 161:320 67 16 1:320 68 16 1:320 69 8  1:1280 70 16 1:320

TABLE 1-14 Test results for S. saprophyticus showing lowest fractionalinhibitory concentration Dilution MIC (μg/ml) ratio MIC for Uva ursiIsolate Nitrofuran- uva ursi combina- Dilution ratio ID toin extracttion* at MIC Result 61 16 1:320 8  1:5120 0.56 62 32 1:160 4 1:320 0.6363 16 1:320 6  1:5120 0.56 64 8 1:160 1 1:320 0.56 65 16 1:320 8 1:640Additivity 66 16 1:320 8  1:5120 0.56 67 16 1:160 2 1:320 0.63 68 161:320 8 1:640 Additivity 69 8  1:1280 0.5  1:2560 0.56 70 16 1:320 81:640 Additivity *When synergy was not observed, the MIC for thecombination was selected based on the nitrofurantoin MIC that providedthe FIC value closest to 0.5. In the case where FIC values were thesame, the MIC for the combination was based on the lowest nitrofurantoinMIC.

D. Summary of Results

The combination of nitrofurantoin with uva ursi was capable of reducingthe MIC of nitrofurantoin against nearly all the isolates tested. Whensynergy was defined as Fractional Inhibitory Concentration (FIC) valueof =0.5, nitrofurantoin and uva ursi were synergistic against strains offour of the seven species tested.

TABLE 2.1 Organisms by which synergy of combination is demonstrated No.of strains where nitrofurantoin in combina- Organism tion with uva ursiwas synergistic (FIC = 0.5) Escherichia coli 6/10 Serratia marcescens4/10 Proteus mirabilis 4/10 Pseudomonas aeruginosa 1/10

The four strains of E. coli that did not demonstrate synergy had FICvalues ranging from 0.56 to 0.75 (between synergy and additivity).

The activity of nitrofurantoin against all strains of S. marcescens wasenhanced in the presence of uva ursi. Four strains had FIC =0.5, and sixstrains had FIC ranging from 0.63 to 1.

Nitrofurantoin and uva ursi were synergistic against four strains of P.mirabilis. In addition, the MIC of nitrofurantoin for one strain wasreduced from 128 μg/ml to 2 μg/ml. Although this was a six doublingdilution decrease in MIC, the FIC was 0.52, which is between synergy andadditivity.

Nitrofurantoin in combination with uva ursi was synergistic against onestrain of P. aeruginosa (MIC reduction from >512 μg/ml to 0.25 μg/ml inthe presence of a 1/80 dilution of uva ursi). Four strains had FIC of 1,demonstrating additivity. Uva ursi had no effect on the antimicrobialactivity of the remaining five strains.

Although none of the drug combinations were synergistic against any ofthe K. pneumoniae isolates tested, the FIC values of four strains were0.75. Uva ursi had no effect on the activity of nitrofurantoin againstone strain and showed additivity for the remaining five strains.

In the case of S. saprophyticus, none of the strains gave FIC =0.5.However, for all organisms the MIC for nitrofurantoin was reduced in thepresence of uva ursi. For example, the MIC of one strain was reducedfrom 8 μg/ml to 0.5 μg/ml in the presence of 1/2,560 dilution of uvaursi (FIC =0.56).

E. faecalis was the least susceptible organism to the nitrofurantoin anduva ursi combinations. None of the strains displayed synergy based onFIC values. Two strains resulted in FIC values between synergy andadditivity (0.75), and one strain demonstrated additivity. Uva ursi hadno effect on the activity of nitrofurantoin against the remaining sevenstrains tested.

In sum, uva ursi enhanced antimicrobial activity against a wide varietyof strains tested. In several cases, the drug combinations weresynergistic, with FIC values of =0.5. There were also many cases wherethe activity of nitrofurantoin was enhanced in the presence of uva ursi,with FIC values ranging from >0.5 to 1 (between synergy and additivity).The extent of synergy was organism-dependent, with E. coli the mostsusceptible and E. faecalis the least susceptible.

VII. Example—Compositions and Methods of Use

All references described herein are hereby incorporated by reference.

All percentages, ratios and proportions herein are by weight, unlessotherwise specified.

The compositions and kits of the present invention are useful in theprevention and treatment of infectious disorders. The followingcomposition and kit examples do not limit the invention. The skilledpractitioner will appreciate that the examples and may be varied basedon the condition being treated and the patient.

Example I.

A tablet form of the present invention is made by combining thefollowing components using conventional mixing and tableting technology.

Component % (by weight) Uva ursi lyophilized extract 17.6 Nitrofurantoinmonohydrate 49.4 Ethylcellulose, 10 100 cps (5% ethanol soln) Starch 16Talc 6 Stearic Acid 1

The uva ursi lyophilized extract and nitrofurantoin monohydrate aregranulated with 5% ethylcellulose in ethanol. The granules are thenpassed through a 12-mesh screen and dried at 120° F. To the driedgranulation is added starch acid. The granulation mixture is passedthrough a 20 mesh screen. To the sieved granulation is added the starchand talc with mixing until uniform. The resultant granulation mixture isthen compressed using conventional tableting processes. The resultingtablets are 250 mg.

A human subject suffering from a urinary tract infection is administeredapproximately 1,000 mg of these tablets, 2 times a day, for 10 days in atypical treatment regimen.

Example II.

A composition according to the present invention is made comprised asfollows:

Component % (by weight) Nitrofuratoin particulates* 1 Nitrofuratoinmonohydrate 0.025 Magnesium aluminum silicate 0.50 Uva ursi^(‡ fluid extract (40% ethanol)) 0.05 Xanthan gum 0.60 Flavorants 0.08Methyl paraben 0.12 Propyl parben 0.02 Purified water 97.605 *Madeaccording to the method described in Example I of U.S. Pat. No.5,178,880. ^(‡)Comprised of Arctostaphylos uva-ursi.

The composition is made by dissolving the methyl paraben, propylparaben, and flavorant in a portion of the water, followed by themagnesium aluminum silicate, to form a “bulk mixture”. The bulk mixtureis then stirred for approximately 1 hour. The xanthan gum is then addedto the bulk mixture, and stirred for approximately 20 minutes. Thenitrofurantoin particulates and uva ursi fluid extract are then added,and the final composition is stirred for approximately 1 hour.

A human subject suffering from acute cystitis is administeredapproximately 20 ml of this suspension, 4 times a day, for 10 days in atypical treatment regimen.

Example III

A composition according the present invention is made according toExample II but an equivalent amount of amount of uva ursi comprising a1:1:1 mixture of Arctostaphylos adenotricha, Arctostaphylos coactylis,and Arctostaphylos uva-ursiis used instead of uva ursi comprisingArctostaphylos uva-ursialone.

Example IV.

A kit for treating an infectious disorder according to the presentinvention is packaged in a single-source container, as follows:

Kit

Macrodantin® tablets at 200 mg

Bearberry leaf tablets at 700 mg

Instructions for use

A human subject suffering from a gastrointestinal tract infection, perthe instructions of the kit, is administered one (1) tablet ofMacrodantin® and Bearberry leaf respectively, three times a day, for 7days. The infection is thereby eradicated.

While particular embodiments of the present invention have beendescribed, it will be apparent to those skilled in the art that Variouschanges and modifications of the present invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of the present invention.

What is claimed is:
 1. A method of treating an infectious disorder, themethod comprising administering nitrofurantoin at least once daily for aperiod of at least 1 day and concurrently administering uva ursi atleast once daily for a period of at least 1 day to a subject in needthereof.
 2. The method of claim 1 wherein the uva ursi is selected fromthe group consisting of Arctostaphylos adenotricha, Arctostaphyloscoactylis and Arctostaphylos uva-ursi.
 3. The method of claim 2 whereinthe uva ursi is Arctostaphylos uva-ursi.
 4. The method of claim 1wherein the nitrofurantoin and uva ursi are administered via a unit doseform.
 5. The method of claim 4 wherein the nitrofurantoin and uva ursiare each administered via a combined unit dose.
 6. The method of claim 4wherein the nitrofurantoin and uva ursi are administered via separateunit doses.
 7. The method of claim 1 wherein the nitrofurantoin isadministered 1-4 times daily, and the uva ursi is concurrentlyadministered 1-4 times daily for at least 2 days.
 8. The method of claim1 wherein the infectious disorder is selected from the group consistingof urinary tract infections, cystitis and pyelonephritis.
 9. A methodaccording to claim 1 wherein the infections disorder is anupper-gastrointestinal disorder mediated by Campylobacter pylori.
 10. Amethod according to claim 9 wherein the disorder is an ulcer.
 11. Amethod of treating an infectious disorder comprising administering akit, wherein the kit comprises: (a) nitrofurantoin in a unit dose form;(b) uva ursi in unit dose form; and (c) a package containing components(a) and (b).
 12. The method of claim 11, wherein the uva ursi isselected from the group consisting of Arctostaphylos adenotricha,Arctostaphylos coactylis and Arctostaphylos uva-ursi.
 13. The method ofclaim 12, wherein the uva ursi is Arctostaphylos uva-ursi.
 14. Themethod of claim 11, wherein the nitrofurantoin and uva ursi areadministered via a unit dose form.
 15. The method of claim 14, whereinthe nitrofurantoin and uva ursi are each administered via a combinedunit dose.
 16. The method of claim 14, wherein the nitrofurantoin anduva ursi are administered via separate unit doses.
 17. The method ofclaim 11, wherein the nitrofurantoin unit dose form is administered 1-4times daily; and the uva ursi unit dose form is concurrentlyadministered 1-4 times daily for at least 2 days.
 18. The method ofclaim 11, wherein the infectious disorder is selected from the groupconsisting of urinary tract infections, cystitis and pyelonephritis. 19.The method according to claim 11, wherein the infections disorder is anupper-gastrointestinal disorder mediated by Campylobacter pylori. 20.The method according to claim 19, wherein the disorder is an ulcer.